Managing adolescent and adult asthma

Sublingual immunotherapy and other updates on adolescent and adult asthma

The prevalence of asthma has been increasing
internationally for several decades. Ireland has one of the highest prevalence
figures for asthma in the world with estimates approaching half a million
people affected. This is disappointing during a time when Ireland has made
significant, slow but steady progress, combating tobacco dependence. The
reasons behind this shift and the consequent significant burden of illness is
not fully understood, but is felt to represent changing environmental factors
such as increasing exposure to allergens and reducing bacterial infections in a
genetically susceptible population.

Burden of disease

Asthma consistently figures in the most common reasons for
hospital admission. Over 90 per cent of these admissions are emergency or
unscheduled. Four times as many admissions are treated and presumably
discharged home from emergency departments. National intelligence data is for
public hospitals only and does not factor in patients attending
insurance-funded acute care units or the increasing activity in emergency rooms
attached to private hospitals.

At least 20 per cent of patients report poor control of
their asthma with impacts on quality-of-life and mortality risk. The Asthma
Society of Ireland reports that children lose five school days while adults
lose seven work days annually as a result of their asthma. The Irish Thoracic
Society reports that mortality rates from asthma increased in the last decade
with a five-year standardised mortality rate of 1.92 and notes that these figures
are a source of concern.

Definition of asthma

Asthma is defined as an inflammatory disease of the
airway. Triggers such as viruses, allergens or exercise, narrow the airway
through luminal obstruction, muscle contraction, and structural changes.
Patients experience airflow limitation with symptoms of cough, breathlessness,
and wheeze.

General principles of treatment

Beta-adrenergic bronchodilators, both short- and
long-acting, relax airway smooth muscle tone, increasing luminal diameter and
reducing airway obstruction. Glucocorticoids, ideally inhaled, reduce the
airway inflammatory response to the asthma trigger, preventing the downstream
cascade series of events responsible for daily symptoms and acute
exacerbations. Long-acting anti-muscarinic (LAMA) bronchodilators are also
licensed for the treatment of asthma as adjunctive therapy in more severe
cases. Immunisation helps mitigate airway infections while identification of
individual triggers such as exercise or inhalation of cold air can help manage specific
triggers for a given patient. The importance of allergen management has been
recognised for many years, but is often limited to avoidance strategies that
are hampered by the ubiquity of sensitising allergens such as house dust mite
or airborne pollens.

The role of immunotherapy

Desensitisation to specific allergens has been feasible
and practised back to the early part of the last century. This approach works
by reducing the inflammatory response to a sensitised antigen and represents an
intervention early in the pathway from triggering agent exposure through to
symptomatic disease. The appeal of this approach was tempered by the need to
administer desensitising doses of antigen parenterally with anaphylaxis,
collapse, and death rare, but much feared adverse events in published reports.
As a result immunotherapy was restricted to specialised centres or clinics with
logistic and medical infrastructure designed to manage such risks safely. An
alternative administration route, specifically sublingually delivering
desensitising doses of antigen topically under the tongue was developed.
Sublingual immunotherapy (SLIT) delivers comparable reductions in allergen
reactivity with a more acceptable side-effect profile. Widespread
implementation of this approach has been hampered by the need to prepare
allergen solutions by specialist manufacturers, which are dispensed in bottles
with a prescribed number of drops of allergen solution administered each day.
Allergen tablets with consistent and biologically standardised doses of
allergen have been developed, which extend the scope of immunotherapy from
specialist clinics to general respiratory and ENT services and into primary
care for GPs with an interest in allergic airway disease. In Ireland this
therapeutic approach was limited to SLIT for grass pollen allergy, however,
house dust mite and tree pollen products are scheduled to be available
imminently.

The Global Initiative for Asthma

The Global Initiative for Asthma (GINA) is an
international self-funded collaboration of major pulmonary and health
organisations dedicated to improving knowledge and treatment of asthma
worldwide. GINA produces a regularly updated set of evidence-based management
principles with the most recent iteration produced in 2019.

Traditionally asthma management has been seen as an
escalating stepwise series of interventions beginning with short-acting
bronchodilators with subsequent increments of inhaled steroids and long-acting
bronchodilators. Adjunctive and systemic therapy is reserved for those with
more severe disease and most likely attending secondary or tertiary care
clinics.

A major change at Step One

The most radical development of the new GINA document is
the abandonment of short-acting bronchodilators alone as acceptable therapy for
the management of asthma. A review of published studies identified that
treatment with short-acting bronchodilators alone was associated with a risk of
sudden exacerbation and death that was mitigated by the use of any inhaled
steroid. As a result Step One of the GINA report now states that patients with
symptoms twice per month or less should use a combined inhaled corticosteroid
and long-acting beta adrenergic bronchodilator (ICS/LABA) as required.
Budesonide/formoterol is the recommended combination as most of the relevant
studies have focused on this pairing, however, the authors note that
beclomethasone/formoterol may also be appropriate.

Step Two

For patients with more frequent or persistent symptoms
regular low-dose ICS are recommended. This can pose some challenges as it
de-emphasises the role of the combined inhaler, which may be reintroduced if
the patient has to proceed to higher treatment steps for adequate symptom
control. The use of ICS/LABA is considered off-licence at this step although studies
have shown non-inferiority when compared with ICS alone. In practice the
patient may oscillate between Step One and Step Two themselves in the absence
of medical supervision. Irrespective, the use of more regular ICS at Step Two
seems key to success as other agents such as leukotriene receptor antagonists,
while useful, appear less efficacious than regular ICS alone for reducing
exacerbation frequency. Finally, economic considerations might favour ICS over
dual agents at this step as exacerbation rates are similar though the time
taken to establish control is shorter when the dual agent is used.

Step Three

Step
Three is unchanged in the 2019 document with a definite role for regular
ICS/LABA. For patients with more than one exacerbation in the previous year,
maintenance and reliever treatment with inhaled budesonide/formoterol or
beclomethasone/formoterol produces superior results to short-acting
bronchodilator and regular ICS with or without a long-acting bronchodilator.
Mixing inhaled ICS/LABA formulations (ie, one ICS/LABA for maintenance and a
different ICS/LABA for relieving) is not recommended and patients using a
maintenance LABA other than formoterol should be prescribed a short-acting
bronchodilator for intermittent use. At this step SLIT may be considered for
patients on appropriate symptomatic therapy with rhinitis who are allergic to
house dust mite, provided FEV1 is >70 per cent.

Step Four

Further
escalations at Step Four include the addition of tiotropium via mist inhaler,
leukotriene antagonists, and increasing the dose of ICS. SLIT is also
considered at this step if it has not been utilised at an earlier stage.

The fundamentals of good asthma management apply across
the spectrum of disease from mild to severe, but particularly beyond Step Two.
These include avoidance of triggers including smoking, inhaler technique,
compliance with treatment, and management of comorbidities such as
gastro-oesophageal reflux disease (GORD). Failure to respond to an appropriate
intervention should prompt a review of diagnostic assumptions and consideration
of other entities such as asthma/COPD overlap syndrome.

The one airway hypothesis

Pathology of the upper airway should also be considered
as part of the management of asthma. Upper airway disease can be considered a
comorbid condition complicating asthma, however, the overlap of triggers and
treatment responses suggests a more intimate association. The one airway
hypothesis was proposed widely in the 1990s and suggested the respiratory epithelium
was a single and continuous structure from the nose right through to the
respiratory bronchioles. Pathophysiological processes are equally pertinent and
prevalent in the upper and lower airways and indeed causally interdependent.
While this seems an oversimplification of the asthmatic airway it does provide
a useful paradigm for the management of more complex asthma patients and is
certainly reflected in the observation of allergic rhinosinusitis preceding an
unstable period of asthmatic airway tone. Upper airway disease is reported by
up to three-quarters of patients with asthma, particularly those with atopic or
allergic disease. Simple nasal washes have been shown to reduce asthma symptom
scores as well as improving upper airway symptoms in suitably selected
patients. Topical steroids, antihistamines, and leukotriene receptor
antagonists can all improve asthma control in part by reducing the upper airway
inflammatory response. SLIT has a role in both upper and lower airway disease
once suitable allergens are identified.

The clinical history and antigen exposure

A clear and focused history will often suggest if allergy
or atopy is contributing to asthma symptoms and may also increase the
confidence of the asthma diagnosis. Sensitisation generally requires repeated
exposure and a careful enquiry into occupational and domestic exposures can
identify suspected antigens. Geography also plays a role. For example, olive
tree pollen poses a significant challenge for Mediterranean populations, but is
seen only under exceptional circumstances in an Irish context. Seasonality and
timing of exposure is also important. Symptoms worsening in summer months are
easily identified as manifestations of grass pollen allergy (typically Timothy
and Rye varieties). Tree pollen allergy is less often considered and can cause
an otherwise inexplicable deterioration in control as early as February. Hazel,
Alder, and Birch are particular considerations though any flowering tree may be
responsible and a modicum of arboreal familiarity can prove invaluable. House
dust mite is a perennial allergen, which can cause year-round symptoms in
heavily exposed susceptible individuals. A surge in symptoms is, however, seen
around autumn when indoor temperatures and humidity increases, favouring the
proliferation of mites and subsequent antigenic load.

Appropriate allergy testing

When an allergic trigger is suspected, confirmatory
testing is required as allergen avoidance can be both costly and
time-consuming. Testing should be guided by history and clinical suspicion as
blanket or otherwise uninformed testing may produce spurious results leading to
ineffective management strategies. As a rule food-based or ingested allergens
are only rarely significant in adults with the vast majority of triggers being
inhaled or aero-allergens. Serologic testing can be performed by measuring IgE
specific antibodies. Total IgE levels may be normal and should not preclude
more detailed analysis if the clinical suspicion remains high. Skin prick
testing is available in many laboratories and correlates closely, but not
exactly with serologic testing. Candidate allergens for testing must be chosen
on the basis of history and clinical suspicion. The choice of serology or skin
prick test will largely be determined by availability and local resources. Skin
prick testing offers the advantage of immediate results at a lower cost and can
easily be performed by suitably trained individuals as part of a clinical
review. Blood IgG measurement has no place in the management of atopic asthma
although precipitating antibodies have a role in the diagnosis of allergic
bronchopulmonary aspergillosis in specialist clinics.

SLIT in clinical practice

SLIT for house dust mite in mild-to-moderate asthma was
associated in one large study with a small, but significant reduction in
inhaled steroid dose at one year without a deterioration in asthma control as
evidenced by lung function, quality-of-life scores, and exacerbation rate.

A second study examined patients with poorly controlled
asthma despite ICS use and found a reduction in the risk of moderate to severe
exacerbation. There were no reports of severe allergic reaction to treatment
although mild-to-moderate oral pruritus was frequently encountered. In practice
the first dose of immunotherapy is administered in a healthcare setting
although subsequent uninterrupted daily treatments appear to be safely
administered at home.

Conclusion

Asthma remains a highly prevalent and burdensome
condition both for patients and healthcare systems. The pattern of disease is
highly variable ranging from sporadic or purely seasonal symptoms through to
highly complex presentations. Care is required as patients can transition from
mild unobtrusive symptoms to life-threatening exacerbations relatively rapidly.
Treatment and advice continues to evolve with new treatment options becoming
available across all levels of care from general practice through to
subspecialty clinics.